The macrophage β-glucan receptor mediates arachidonate release induced by zymosan: Essential role for Src family kinases

Yeast-derived zymosan beads are among the classical agents used to induce sterile inflammatory responses in experimental animals and macrophage activation in cell culture. In macrophages the cytosolic phospholipase A2 becomes activated, leading to mobilization of arachidonate and the generation of prostaglandins and leukotrienes. Although zymosan can interact with several receptors it has not been unequivocally demonstrated which interaction is required for induction of the eicosanoid response.We have compared arachidonate release induced in primary mouse macrophages by zymosan and particulate β-glucan and found striking similarities. The similarities include the effects of dectin-1 antagonists (soluble β-glucan and laminarin) and of inhibitors of Src family kinases, the Tec kinase Btk, phosphatidylinositol 3-kinase and the Map kinases ERK and p38. Furthermore, particulate β-glucan was equally effective as zymosan in causing phosphorylation of phospholipase Cγ2, arguing that both agents act via the β-glucan receptor dectin-1 and that the above signal components are engaged down-stream of that receptor. Suggestive evidence for a role of the scaffold adaptor Gab2 is also presented.